Structure based molecular inhibition of Caspase-8 for treatment of multi-neurodegenerative diseases using known natural compounds

Abstract

Neurodegenerative disorders are often associated with excessive neuronal apoptosis. It is well known that apoptosis is regulated by some intracellular proteases, such as, Caspases (cysteine-dependent, aspartate-specific proteases). In fact, Caspase-8 which is an initiator caspase, has been identified as a key mediator of neuronal apoptosis. In addition, Caspase-8 is found to be coupled with the regulation of various neurodegenerative disorders including Alzheimer׳s disease (AD), Parkinson׳s disease (PD), Huntington׳s Diseases (HD) and Dentatorubral Pallidoluysian Atrophy (DRPLA). Caspase-8 inhibition may provide an effective means of treatment for multiple neurodegenerative disorders. Therefore, the present study describes the molecular interaction of some selected natural compounds with known anti neurodegenerative properties with Caspase-8. Docking between Caspase-8 and each of these compounds (separately) was performed using ‘Autodock4.2’. Out of all the selected compounds, rosmarinic acid and curcumin proved to be the most potent inhibitors of Caspase-8 with binding energy (ΔG) of -7.10 Kcal/mol and -7.08 Kcal/mol, respectively. However, further in vitro and in vivo studies are needed to validate the anti-neurodegenerative potential of these compounds.

Study of Caspase 8 Inhibition for the Management of Alzheimer’s Disease: A Molecular Docking and Dynamics Simulation

“…In previous studies, huperzine A appeared to have positive effects on the improvement of cognitive function and curing of AD [19], and quercetin showed significant protective effects on neuronal cells in AD [20,21]. The free energies of human caspase 8 binding with huperzine A and quercetin have been reported as −4.28 kcal/mol and −4.89 kcal/mol, respectively [22].…”

Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests

“…A loss-of-function mutation of ARNT2 in humans results in Webb–Dattani syndrome, with characteristic features such as microcephaly, visual impairment and urinary abnormalities (Webb et al 2013 ). Caspase 8 was up-regulated by the HDACis and has been described to regulate neuronal apoptosis involved in neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Huntington’s disease in humans (Ahmad et al 2014 ). In conclusion, the involvement of the diagnostic genes deregulated by mercurials and HDACis by both test systems in developmental toxicity in humans and experimental animals has been well established.…”

Identification of common therapeutic targets for selected neurodegenerative disorders: An in silico approach

“…The CAG repeats are located in the coding regions of the respective responsible genes and translated into polyglutamine. Activated CASP8 was previously reported to be present within insoluble fractions of DRPLA brains [57].…”

“…The activation of CASP8 in inflamed microglia prevents their death by necroptosis; thus, caspase-8 inhibitors may protect neurons in the inflamed brain by selectively killing activated microglia [57].…”